Risperidone has been shown to be effective in decreasing serious behavioral problems in children with autism spectrum disorders (McCracken et al., 2002;Shea et al., 2004;Nagaraj et al., 2006;Pandina et al., 2006). However, only two-thirds of children respond to this treatment and many have significant side effects. Our ultimate goal for this project is to develop pretreatment methods to predict response, appropriate dosage and serious side effects of risperidone treatment. We will identify 50 children (4 to 18 years old) with autism who also have serious behavioral problems and treat them with risperidone. Blood samples will be obtained prior to treatment and after eight weeks of treatment. Treatment efficacy will be assessed using the Irritability subscale of the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement scale (CGI-I). RNA expression from blood will be assessed using Affymetrix oligonucleotide microarrays and RT-PCR. Based on preliminary studies, we expect to demonstrate a change in RNA expression in the blood of children with autism with severe behavioral problems after eight weeks of risperidone treatment compared to prior to treatment. We will determine whether those children with autism and severe behavioral problems who significantly improve by 8 weeks of risperidone treatment have different RNA expression profiles compared to children with autism whose behaviors do not improve. We will also determine whether RNA expression profiles in blood prior to treatment predict behavioral improvement or not after 8 weeks of treatment with risperidone. We will confirm the microarray results with qRT-PCR and use these to predict the risperidone responders and the risperidone non-responders in the second half of the sample to determine if specific genes do indeed predict response. The overarching hypothesis that drives this pilot R21 project is that the efficacy, dose and occurrence of side effects of risperidone for the treatment of serious behavioral symptoms in children with autism will be reflected in specific gene expression/RNA profiles in the blood prior to treatment. PUBLIC HEALTH RELEVANCE: Risperidone, the most studied atypical antipsychotic used in children, has been shown to improve severe behavioral symptoms in over half of children with autism with these problems. However, not all children with autism and severe behavioral problems respond to risperidone, and for a few, it has significant side effects. Blood genomic profiles are shown to predict medication response for disorders such as cancer and epilepsy. This re-submitted exploratory or discovery R21 study proposes to use blood genomic profiles before and after risperidone treatment in children with autism and severe behavioral problems to determine if the profiles can predict response to treatment. The ultimate goal of this line of research is to develop methods to predict which medications work for which child before initiating treatment, to predict which child might develop particular side effects, and to identify new treatment targets for future medication development.